A liposome is a spherical vesicle having at least one lipid bilayer. It has been used as a targeted drug carrier and belongs to a new formulation of targeted drug delivery system. It can embed powder or solution of a drug in particle with a diameter at micron or nanometer level, the particle is similar to a bilayer micro vesicle of a biological membrane structure and has good biocompatibility. The reason for calling it targeted drug delivery system is, on one hand, after the surface-unmodified liposome enters a human body, it is usually susceptible to be phagocytized by the reticulo endothelial system, thereby activating the body's own immune function and changing the distribution of the embedded drug in the human body, which leads to the drug mainly accumulated in liver, spleen and other tissues and organs. Due to the enhanced permeability and retention effect of tumors (EPR effect), the liposome with a particle size at nanometer level can accumulate effectively at the tumor sites, this property can be called passive target of the liposome. On the other hand, the surface of the liposome can be modified by specific ligands in a covalent or non-covalent manner. The ligands include antibodies, polypeptides, aptamers, glycosyl and small molecules and so on. The liposome is efficiently absorbed by specific targeted cells through an interaction between ligands and receptors, which is called initiative target, often compared to “biological missile”. The targeted drug delivery capability of the liposome can increase the therapeutic index of the drug, reduce the dosage and the toxicity of the drug.
A structure of the liposome is different from a micelle that is constructed by the surfactant. The latter is composed of a monomolecular layer, while the liposome is composed of bilayer which can embed a lipophilic drug or a water-soluble drug. The main components of the liposome are lipid (e.g., phospholipid) and cholesterol. Phospholipid is an amphiphilic material and contains phosphate groups and amino-containing basic groups (both hydrophilic), and two relatively long hydrophobic hydrocarbon chains. Cholesterol is an amphipathic material and has both a hydrophobic group and a hydrophilic group, but its hydrophobicity is stronger than its hydrophilicity. When the phospholipid forms a liposome, there are two hydrophobic chains pointing to the interior, the hydrophilic groups are on both inside and outside surfaces of the membrane. The phospholipid bilayer constitutes a closed compartment, which contains an aqueous solution. The aqueous solution in the compartment is surrounded by the phospholipid bilayer and independent, the phospholipid bilayer forms a vesicle and is separated by the aqueous medium. The cholesterol increases the stability of the liposome membrane, and other excipients have special functional effects.
The main components of a conventional liposome are phospholipid and cholesterol forming the liposome's membrane. The main components (except for the Taxol drug) of a paclitaxel liposome supplied by Cisco Nanjing (marketed as “Paclitaxel Liposome”, herein also referred to simply as “paclitaxel”) include lecithin (first main component), cholesterol (second main component), threonine (an amino acid generally used as an antioxidant or a buffer reagent), and glucose (glucide generally used as a freeze-dried excipient or a cryoprotectant). Other excipients can also be added into the liposome, such as adding a heat-sensitive excipient to prepare a heat-sensitive liposome, adding a pH-sensitive excipient to prepare a pH-sensitive liposome, adding a cation or an anion to prepare a cationic liposome or an anionic liposome, or adding a surfactant etc. According to different purposes, different excipients are added. Generally, the liposome before frozen dried has the phospholipid (generally with a proportion of 50% to 95%) and the cholesterol (about 5% to 50%) as main components, but during the process of freeze-drying, a certain amount of excipient will be added according to the specific conditions. Depending on different uses of the liposome, the proportion of the added excipient is greatly different. Some do not need to add excipients during freeze-drying, while some even require an addition of 50% excipients during freeze-drying. In addition, there are many modified phospholipids in the market at present, such as phospholipid modified by PEG or amino acid, which contains very small amounts of excipients. Therefore, mutual reference does not have significant meaning between liposomes with different uses and in different types since the specific components and the amount of each component are greatly different (Note: the percentage mentioned above refers to a percentage of each component relative to the total mass of the raw materials of the liposome).
There are corresponding technical requirements for preparation due to differences in physical and chemical properties of different types of drugs, such as structure, solubility, stability and so on. Meanwhile, it is necessary to continue improving technology, membrane materials, pilot scaling and other aspects. There are eight main indicators to evaluate the quality of liposomes, including morphology and particle size of liposomes (including dispersion), encapsulation efficiency, drug loading, burst and permeability, release in vitro, oxidation degree of the phospholipids, residual of organic solvent and functional evaluation in vivo and in vitro. But over all, the present liposomes still have shortcomings such as that the target-specific ability needs to be further improved, encapsulation efficiency is low, stability is poor and the process for preparation is complicated etc.
Therefore, it is always a key point and direction of the liposome to research a liposome with high efficiency, safety, stability, enhanced targetability, good uniformity, stable and reliable quality, and simple process for preparation.
Ginsenoside is a material having special amphipathic property with a glycosyl in the hydrophilic end and a long terminal chain in the lipophilic end. Ginsenoside has wide pharmaceutical uses, for example that ginsenoside F4 and Rg6 are used for treating lymphoma, ginsenoside Rg3 is used for treating dysmenorrhea and vitiligo, ginsenoside Rh1 can be used to improve steroid resistant induced by using dexamethasone and increase the anti-inflammatory effect of the dexamethasone, the ginsenoside Rb1 can be used to prevent and treat hypertension (see CN201310165926, CN201310165907, CN201210501652, CN201310011400 and CN201210486959). CN201210151597.0 discloses a liposome of ginsenoside Rg3 and its preparation method. The liposome of ginsenoside Rg3 is obtained by encapsulating the drug ginsenoside Rg3 into a liposome, which significantly increases the absorption and bioavailability of ginsenoside Rg3 and enhances its targetability to the tumor tissues, therefore, improves the drug efficacy.
In the prior art, there is no report on that the ginsenoside, as a liposome membrane material and meanwhile a targeted material and a drug, can be used to prepare a blank liposome and encapsulate drugs and other components.